CHAPTER 14MENDEL AND THE GENE IDEA

CHAPTER 14 MENDEL AND THE GENE IDEA

Section A: Gregor Mendel’s Discoveries

1. Mendel brought an experimental and quantitative approach to genetics

2. By the law of segregation, the two alleles for a character are packaged into

separate gametes

3. By the law of independent assortment, each pair of alleles segregates into

gametes independently

4. Mendelian inheritance reflects rules of probability

5. Mendel discovered the particulate behavior of genes: a review

• Every day we observe heritable variations (eyes of brown, green, blue, or gray) among individuals in a population.

• These traits are transmitted from parents to offspring.

• One mechanism for this transmission is the “blending” hypothesis.– This hypothesis proposes that the genetic

material contributed by each parent mixes in a manner analogous to the way blue and yellow paints blend to make green.

– Over many generations, a freely mating population should give rise to a uniform population of individuals.

Introduction

• However, the “blending” hypothesis appears incorrect as everyday observations and the results of breeding experiments contradict its predictions.

• An alternative model, “particulate” inheritance, proposes that parents pass on discrete heritable units - genes - that retain their separate identities in offspring.– Genes can be sorted and passed on,

generation after generation, in undiluted form.• Modern genetics began in an abbey garden,

where a monk names Gregor Mendel documented the particulate mechanism of inheritance.

• Mendel grew up on a small farm in what is today the Czech Republic.

• In 1843, Mendel entered an Augustinian monastery.

• He studied at the University of Vienna from 1851 to 1853 where he was influenced by a physicist who encouraged experimentation and the application of mathematics to science and a botanist who aroused Mendel’s interest in the causes of variation in plants.

• These influences gelled in Mendel’s experiments.

1. Mendel brought an experimental and quantitative approach to genetics

• After the university, Mendel taught at the Brunn Modern School and lived in the local monastery.

• The monks at this monastery had a long tradition of interest in the breeding of plants, including peas.

• Around 1857, Mendel began breeding garden peas to study inheritance.

• Pea plants have several advantages for genetics.– Pea plants are available in many varieties with

distinct heritable features (characters) with different variants (traits).

– Another advantage of peas is that Mendel had strict control over which plants mated with which.

– Each pea plant has male (stamens) and female (carpal) sexual organs.

– In nature, pea plants typically self-fertilize, fertilizing ova with their own sperm.

– However, Mendel could also move pollen from one plant to another to cross-pollinate plants.

• In a typical breeding experiment, Mendel would cross-pollinate (hybridize) two contrasting, true-breeding pea varieties.– The true-breeding parents are the P

generation and their hybrid offspring are the F1 generation.

• Mendel would then allow the F1 hybrids to self-pollinate to produce an F2 generation.

• It was mainly Mendel’s quantitative analysis of F2 plants that revealed the two fundamental principles of heredity: the law of segregation and the law of independent assortment.

• If the blending model were correct, the F1 hybrids from a cross between purple-flowered and white-flowered pea plants would have pale purple flowers.

• Instead, the F1 hybrids all have purple flowers, just a purple as the purple-flowered parents.

2. By the law of segregation, the two alleles for a characters are packaged into separate

gametes

• When Mendel allowed the F1 plants to self-fertilize, the F2 generation included both purple-flowered and white-flowered plants.

– The white trait, absent in the F1, reappeared in the F2.

• Based on a large sample size, Mendel recorded 705 purple-flowered F2 plants and 224 white-flowered F2 plants from the original cross. Fig. 14.2

• This cross produced a three purple to one white ratio of traits in the F2 offspring,

• Mendel reasoned that the heritable factor for white flowers was present in the F1 plants, but it did not affect flower color.– Purple flower is a dominant trait and white

flower is a recessive trait.• The reappearance of white-flowered plants in the

F2 generation indicated that the heritable factor for the white trait was not diluted or “blended” by coexisting with the purple-flower factor in F1 hybrids.

• Mendel found similar 3 to 1 ratios of two traits among F2 offspring when he conducted crosses for six other characters, each represented by two different varieties.

• For example, when Mendel crossed two true-breeding varieties, one of which produced round seeds, the other of which produced wrinkled seeds, all the F1 offspring had round seeds, but among the F2 plants, 75% of the seeds were round and 25% were wrinkled.

• Mendel developed a hypothesis to explain these results that consisted of four related ideas.

1. Alternative version of genes (different alleles) account for variations in inherited characters.– Different alleles vary somewhat in the sequence of

nucleotides at the specific locus of a gene.• The purple-flower

allele and white-flower allele are two DNA variations at the flower-color locus.

2. For each character, an organism inherits twoalleles, one from each parent.– A diploid organism inherits one set of

chromosomes from each parent.– Each diploid organism has a pair of

homologous chromosomes and therefore two copies of each locus.

• These homologous loci may be identical, as in the true-breeding plants of the P generation.

• Alternatively, the two alleles may differ

– In the flower-color example, the F1 plants inherited a purple-flower allele from one parent and a white-flower allele from the other.

3. If two alleles differ, then one, the dominant allele, is fully expressed in the the organism’s appearance.

• The other, the recessive allele, has no noticeable effect on the organism’s appearance.– Mendel’s F1 plants had purple flowers because

the purple-flower allele is dominant and the white-flower allele is recessive.

4. The two alleles for each character segregate (separate) during gamete production.

• This segregation of alleles corresponds to the distribution of homologous chromosomes to different gametes in meiosis.– If an organism has identical allele for a

particular character, then that allele exists as a single copy in all gametes.

– If different alleles are present, then 50% of the gametes will receive one allele and 50% will receive the other.

• The separation of alleles into separate gametes is summarized as Mendel’s law of segregation.

• Mendel’s law of segregation accounts for the 3:1 ratio that he observed in the F2 generation.

• The F1 hybrids will produce two classes of gametes, half with the purple-flower allele and half with the white-flower allele.

• During self-pollination, the gametes of these two classes unite randomly.

• This can produce four equally likely combinations of sperm and ovum.

• A Punnett square predicts the results of a genetic cross

between individuals of known genotype.

• A Punnett square analysis of the flower-color example demonstrates Mendel’s model.– One in four F2 offspring will inherit two white-

flower alleles and produce white flowers.

– Half of the F2 offspring will inherit one white-flower allele and one purple-flower allele and produce purple flowers.

– One in four F2 offspring will inherit two purple-flower alleles and produce purple flowers too.

• Mendel’s model accounts for the 3:1 ratio in the F2 generation

• Genetics has some unique, useful vocabulary.• An organism with two identical alleles for a

character is homozygous for that character.• Organisms with two different alleles for a character

is heterozygous for that character.• A description of an organism’s traits is its

phenotype.• A description of its genetic makeup is its

genotype.– Two organisms can have the same phenotype

but have different genotypes if one is homozygous dominant and the other is heterozygous.

• For flower color in peas, both PP and Pp plants have the same phenotype (purple) but different genotypes (homozygous and heterozygous).

• The only way to produce a white phenotype is to be homozygous recessive (pp) for the flower-color gene.

• It is not possible to predict the genotype of an organism with a dominant phenotype.– The organism must have one dominant allele,

but it could be homozygous dominant or heterozygous.

• A test cross, breeding a homozygous recessive with dominant phenotype, but unknown geneotype,can determine the identity of the unknown allele.

• Mendel’s experiments that followed the inheritance of flower color or other characters focused on only a single character via monohybrid crosses.

• He conduced other experiments in which he followed the inheritance of two different characters, a dihybrid cross.

3. By the law of independent assortment, each pair of alleles segregates into gametes

independently

• In one dihybrid cross experiment, Mendel studied the inheritance of seed color and seed shape.– The allele for yellow seeds (Y) is dominant to

the allele for green seeds (y).– The allele for round seeds (R) is dominant to

the allele for wrinkled seeds (r).

• Mendel crossed true-breeding plants that had yellow, round seeds (YYRR) with true-breeding plants that has green, wrinkled seeds (yyrr).

• One possibility is that the two characters are transmitted from parents to offspring as a package.– The Y and R alleles and y and r alleles stay

together.

• If this were the case, the F1 offspring would produce yellow, round seeds.

• The F2 offspring would produce two phenotypes in a 3:1 ratio, just like a monohybrid cross.

• This was not consistentwith Mendel’s results.

• An alternative hypothesis is that the two pairs of alleles segregate independently of each other.– The presence of one specific allele for one trait

has no impact on the presence of a specific allele for the second trait.

• In our example, the F1 offspring would still produce yellow, round seeds.

• However, when the F1’s produced gametes, genes would be packaged into gametes with all possible allelic combinations.– Four classes of gametes (YR, Yr, yR, and yr)

would be produced in equal amounts.

• When sperm with four classes of alleles and ova with four classes of alleles combined, there would be 16 equally probable ways in which the alleles can combine in the F2 generation.

• These combinations produce four distinct phenotypes in a 9:3:3:1 ratio.

• This was consistent with Mendel’s results.

• Mendel repeated the dihybrid cross experiment for other pairs of characters and always observed a 9:3:3:1 phenotypic ration in the F2 generation.

• Each character appeared to be inherited independently.

• The independent assortment of each pair of alleles during gamete formation is now called Mendel’s law of independent assortment.

• One other aspect that you can notice in the dihybrid cross experiment is that if you follow just one character, you will observe a 3:1 F2 ratio for each, just as if this were a monohybrid cross.

• Mendel’s laws of segregation and independent assortment reflect the same laws of probability that apply to tossing coins or rolling dice.

• The probability scale ranged from zero (an event with no chance of occurring) to one (an event that is certain to occur).– The probability of tossing heads with a normal

coin is 1/2.– The probability of rolling a 3 with a six-sided die

is 1/6, and the probability of rolling any other number is 1 - 1/6 = 5/6.

4. Mendelian inheritance reflects rule of probability

• When tossing a coin, the outcome of one toss has no impact on the outcome of the next toss.

• Each toss is an independent event, just like the distribution of alleles into gametes.– Like a coin toss, each ovum

from a heterozygous parent has a 1/2 chance of carrying the dominant allele and a 1/2 chance of carrying the recessive allele.

– The same odds apply to the sperm.

• We can use the rule of multiplication to determine the chance that two or more independent events will occur together in some specific combination.– Compute the probability of each independent event.– Then, multiply the individual probabilities to obtain the

overall probability of these events occurring together.– The probability that two coins tossed at the same time

will land heads up is 1/2 x 1/2 = 1/4.– Similarly, the probability that a heterogyzous pea plant

(Pp) will produce a white-flowered offspring (pp) depends on an ovum with a white allele mating with a sperm with a white allele.

– This probability is 1/2 x 1/2 = 1/4.

• The rule of multiplication also applies to dihybrid crosses.– For a heterozygous parent (YyRr) the

probability of producing a YR gamete is 1/2 x 1/2 = 1/4.

– We can use this to predict the probability of a particular F2 genotype without constructing a 16-part Punnett square.

– The probability that an F2 plant will have a YYRR genotype from a heterozygous parent is 1/16 (1/4 chance for a YR ovum and 1/4 chance for a YR sperm).

• The rule of addition also applies to genetic problems.

• Under the rule of addition, the probability of an event that can occur two or more different ways is the sum of the separate probabilities of those ways.– For example, there are two ways that F1

gametes can combine to form a heterozygote.• The dominant allele could come from the sperm and

the recessive from the ovum (probability = 1/4).• Or, the dominant allele could come from the ovum

and the recessive from the sperm (probability = 1/4).• The probability of a heterozygote is 1/4 + 1/4 = 1/2.

• We can combine the rules of multiplication and addition to solve complex problems in Mendelian genetics.

• Let’s determine the probability of finding two recessive phenotypes for at least two of three traits resulting from a trihybrid cross between pea plants that are PpYyRr and Ppyyrr.– There are five possible genotypes that fulfill

this condition: ppyyRr, ppYyrr, Ppyyrr, PPyyrr, and ppyyrr.

– We would use the rule of multiplication to calculate the probability for each of these genotypes and then use the rule of addition to pool the probabilities for fulfilling the condition of at least two recessive trait.

• The probability of producing a ppyyRr offspring:– The probability of producing pp = 1/2 x 1/2 = 1/4.– The probability of producing yy = 1/2 x 1 = 1/2.– The probability of producing Rr = 1/2 x 1 = 1/2. – Therefore, the probability of all three being

present (ppyyRr) in one offspring is 1/4 x 1/2 x 1/2 = 1/16.

• For ppYyrr: 1/4 x 1/2 x 1/2 = 1/16.• For Ppyyrr: 1/2 x 1/2 x 1/2 = 2/16• for PPyyrr: 1/4 x 1/2 x 1/2 = 1/16• for ppyyrr: 1/4 x 1/2 x 1/2 = 1/16• Therefore, the chance of at least two

recessive traits is 6/16.

• While we cannot predict with certainty the genotype or phenotype of any particular seed from the F2 generation of a dihybrid cross, we can predict the probabilities that it will fit a specific genotype of phenotype.

• Mendel’s experiments succeeded because he counted so many offspring and was able to discern this statistical feature of inheritance and had a keen sense of the rules of chance.

5. Mendel discovered the particulate behavior of genes: a review

• Mendel’s laws of independent assortment and segregation explain heritable variation in terms of alternative forms of genes that are passed along according to simple rule of probability.

• These laws apply not just to garden peas, but to all other diploid organisms that reproduce by sexual reproduction.

• Mendel’s studies of pea inheritance endures not only in genetics, but as a case study of the power of scientific reasoning using the hypothetico-deductive approach.

CHAPTER 14MENDEL AND THE GENE IDEA

Section B: Extending Mendelian Genetics

1. The relationship between genotype and phenotype is rarely simple

• In the 20th century, geneticists have extended Mendelian principles not only to diverse organisms, but also to patterns of inheritance more complex than Mendel described.

• In fact, Mendel had the good fortune to choose a system that was relatively simple genetically.– Each character (but one) is controlled by a single

gene.– Each gene has only two alleles, one of which is

completely dominant to the other.

1. The relationship between genotype and phenotype is rarely simple

• The heterozygous F1 offspring of Mendel’s crosses always looked like one of the parental varieties because one allele was dominant to the other.

• However, some alleles show incomplete dominance where heterozygotes show a distinct intermediate phenotype, not seen in homozygotes.– This is not blended inheritance because the traits are

separable (particulate) as seen in further crosses.– Offspring of a cross between heterozygotes will show

three phenotypes: both parentals and the heterozygote. – The phenotypic and genotypic ratios are identical, 1:2:1.

• A clear example of incomplete dominance is seen in flower color of snapdragons.– A cross between a

white-flowered plant and a red-flowered plant will produce all pink F1 offspring.

– Self-pollination of the F1 offspring produces

25% white, 25% red, and 50% pink offspring.

• Complete and incomplete dominance are part of a spectrum of relationships among alleles.

• At the other extreme from complete dominance is codominance in which two alleles affect the phenotype in separate, distinguishable ways.– For example, the M, N, and MN blood groups

of humans are due to the presence of two specific molecules on the surface of red blood cells.

– People of group M (genotype MM) have one type of molecule on their red blood cells, people of group N (genotype NN) have the other type, and people of group MN (genotype MN) have both molecules present.

• The dominance/recessiveness relationships depend on the level at which we examine the phenotype.– For example, humans with Tay-Sachs disease lack a

functioning enzyme to metabolize gangliosides (a lipid) which accumulate in the brain, harming brain cells, and ultimately leading to death.

– Children with two Tay-Sachs alleles have the disease.– Heterozygotes with one working allele and homozygotes

with two working alleles are “normal” at the organismal level, but heterozygotes produce less functional enzyme.

– However, both the Tay-Sachs and functional alleles produce equal numbers of enzyme molecules, codominant at the molecular level.

• Dominant alleles do not somehow subdue a recessive allele.

• It is in the pathway from genotype to phenotype that dominance and recessiveness come into play.– For example, wrinkled seeds in pea plants with two

copies of the recessive allele are due to the accumulation of monosaccharides and excess water in seeds because of the lack of a key enzyme.• The seeds wrinkle when they dry.

– Both homozygous dominants and heterozygotes produce enough enzyme to convert all the monosaccharides into starch and form smooth seeds when they dry.

• Because an allele is dominant does not necessarily mean that it is more common in a population than the recessive allele.– For example, polydactyly, in which individuals

are born with extra fingers or toes, is due to an allele dominant to the recessive allele for five digits per appendage.

– However, the recessive allele is far more prevalent than the dominant allele in the population.• 399 individuals out of 400 have five digits per

appendage.

• Dominance/recessiveness relationships have three important points.

1. They range from complete dominance, though various degrees of incomplete dominance, to codominance.

2. They reflect the mechanisms by which specific alleles are expressed in the phenotype and do not involve the ability of one allele to subdue another at the level of DNA.

3. They do not determine or correlate with the relative abundance of alleles in a population.

• Most genes have more than two alleles in a population.

• The ABO blood groups in humans are determined by three alleles, IA, IB, and I.– Both the IA and IB alleles are dominant to the i

allele – The IA and IB alleles are codominant to each

other.

• Because each individual carries two alleles, there are six possible genotypes and four possible blood types.

– Individuals that are IA IA or IA i are type A and place type A oligosaccharides on the surface of their red blood cells.

– Individuals that are IB IB or IB i are type B and place type B oligosaccharides on the surface of their red blood cells.

– Individuals that are IA IB are type AB and place both type A and type B oligosaccharides on the surface of their red blood cells.

– Individuals that are ii are type O and place neither oligosaccharide on the surface of their red blood cells.

• Matching compatible blood groups is critical for blood transfusions because a person produces antibodies against foreign blood factors.– If the donor’s blood has an A or B

oligosaccharide that is foreign to the recipient, antibodies in the recipient’s blood will bind to the foreign molecules, cause the donated blood cells to clump together, and can kill the recipient.

• The genes that we have covered so far affect only one phenotypic character.

• However, most genes are pleiotropic, affecting more than one phenotypic character.– For example, the wide-ranging symptoms of

sickle-cell disease are due to a single gene.

• Considering the intricate molecular and cellular interactions responsible for an organism’s development, it is not surprising that a gene can affect a number of an organism’s characteristics.

• In epistasis, a gene at one locus alters the phenotypic expression of a gene at a second locus.– For example, in mice and many other

mammals, coat color depends on two genes.– One, the epistatic gene, determines whether

pigment will be deposited in hair or not.• Presence (C) is dominant to absence (c).

– The second determines whether the pigment to be deposited is black (B) or brown (b).• The black allele is dominant to the brown allele.

– An individual that is cc has a white (albino) coat regardless of the genotype of the second gene.

• A cross between two black mice that are heterozygous (BbCc) will follow the law of independent assortment.

• However, unlike the 9:3:3:1 offspring ratio of an normal Mendelian experiment, the ratio is nine black, three brown, and four white.

• Some characters do not fit the either-or basis that Mendel studied.

• Quantitative characters vary in a population along a continuum

• These are usually due to polygenic inheritance, the additive effects of two or more genes on a single phenotypic character.– For example, skin color in humans is controlled

by at least three different genes.– Imagine that each gene has two alleles, one

light and one dark, that demonstrate incomplete dominance.

– An AABBCC individual is dark and aabbcc is light.

• A cross between two AaBbCc individuals (intermediate skin shade) would produce offspring covering a wide range of shades.– Individuals with

intermediate skin shades would be the most likely offspring, but very light and very dark individuals are possible as well.

– The range of phenotypes forms a normal distribution.

• Phenotype depends on environment and genes.– A single tree has leaves that vary in size, shape, and

greenness, depending on exposure to wind and sun.– For humans, nutrition influences height, exercise alters

build, sun-tanning darkens the skin, and experience improves performance on intelligence tests.

– Even identical twins, genetic equals, accumulate phenotypic differences as a result of their unique experiences.

• The relative importance of genes and the environment in influencing human characteristics is a very old and hotly contested debate.

• The product of a genotype is generally not a rigidly defined phenotype, but a range of phenotypic possibilities, the norm of reaction, that are determined by the environment.– In some cases the norm of reaction has no breadth (for

example, blood type).• Norms of reactions are broadest for polygenic characters.

– For these multifactorial characters, environment contributes to their quantitative nature.

• A reductionist emphasis on single genes and single phenotypic characters presents an inadequate perspective on heredity and variation.

• A more comprehensive theory of Mendelian genetics must view organisms as a whole.

• Phenotype has been used to this point in the context of single characters, but it is also used to describe all aspects of an organism.

• Genotype can refer not just to a single genetic locus, but to an organism’s entire genetic makeup.

• An organism’s phenotype reflects its overall genotype and unique environmental history.

CHAPTER 14 MENDEL AND THE GENE IDEA

Section C: Mendelian Inheritance in Humans

1. Pedigree analysis reveals Mendelian patterns in human inheritance

2. Many human disorders follow Mendelian patterns of inheritance

3. Technology is providing news tools for genetic testing and counseling

• While peas are convenient subjects for genetic research, humans are not.– The generation time is too long, fecundity too

low, and breeding experiments are unacceptable.

• Yet, humans are subject to the same rules regulating inheritance as other organisms.

• New techniques in molecular biology have lead to many breakthrough discoveries in the study of human genetics.

Introduction

• Rather than manipulate mating patterns of people, geneticists analyze the results of matings that have already occurred.

• In a pedigree analysis, information about the presence/absence of a particular phenotypic trait is collected from as many individuals in a family as possible and across generations.

• The distribution of these characters is then mapped on the family tree.

1. Pedigree analysis reveals Mendelian patterns in human inheritance

– For example, the occurrence of widows peak (W) is dominant to a straight hairline (w).

– The relationship among alleles can be integrated with the phenotypic appearance of these traits to predict the genotypes of members of this family.

• For example, if an individual in the third generation lacks a widow’s peak, but both her parents have widow’s peaks, then her parents must be heterozygous for that gene

• If some siblings in the second generation lack a widow’ peak and one of the grandparents (first generation) also lacks one, then we know the other grandparent must be heterozygous and we can determine the genotype of almost all other individuals.

– We can use the same family tree to trace the distribution of attached earlobes (f), a recessive characteristic.

– Individuals with a dominant allele (F) have free earlobes.

– Some individuals may be ambiguous, especially if they have the dominant phenotype and could be heterozygous or homozygous dominant.

• A pedigree can help us understand the past and to predict the future.

• We can use the normal Mendelian rules, including multiplication and addition, to predict the probability of specific phenotypes.– For example, these rules could be used to predict

the probability that a child with WwFf parents will have a widow’s peak and attached earlobes.• The chance of having a widow’s peak is 3/4 (1/2 [WW]

+ 1/4 [Ww]).• The chance of having attached earlobes is 1/4 [ff].• This combination has a probability of 3/4 + 1/4 = 3/16.

• Thousands of genetic disorders, including disabling or deadly hereditary diseases, are inherited as simple recessive traits.– These range from the relatively mild (albinism) to

life-threatening (cystic fibrosis).• The recessive behavior of the alleles occurs

because the allele codes for either a malfunctioning protein or no protein at all.– Heterozygotes have a normal phenotype

because one “normal” allele produces enough of the required protein.

2. Many human disorders follow Mendelian patterns of inheritance

• A recessively inherited disorder shows up only in homozygous individuals who inherit one recessive allele from each parent.

• Individuals who lack the disorder are either homozgyous dominant or heterozygotes.

• While heterozygotes may have no clear phenotypic effects, they are carriers who may transmit a recessive allele to their offspring.

• Most people with recessive disorders are born to carriers with normal phenotypes.– Two carriers have a 1/4 chance of having a child

with the disorder, 1/2 chance of a carrier, and 1/4 free.

• Genetic disorders are not evenly distributed among all groups of humans.

• This results from the different genetic histories of the world’s people during times when populations were more geographically (and genetically) isolated.

• One such disease is cystic fibrosis which strikes one of every 2,500 whites of European descent.– One in 25 whites is a carrier.– The normal allele codes for a membrane protein that

transports Cl- between cells and the environment.– If these channels are defective or absent, there are

abnormally high extracellular levels of chloride that causes the mucus coats of certain cells to become thicker and stickier than normal.

– This mucus build-up in the pancreas, lungs, digestive tract, and elsewhere favors bacterial infections.

– Without treatment, affected children die before five, but with treatment can live past their late 20’s.

• Tay-Sachs disease is another lethal recessive disorder.– It is caused by a dysfunctional enzyme that

fails to break down specific brain lipids.– The symptoms begin with seizures, blindness,

and degeneration of motor and mental performance a few months after birth.

– Inevitably, the child dies after a few years.– Among Ashkenazic Jews (those from central

Europe) this disease occurs in one of 3,600 births, about 100 times greater than the incidence among non-Jews or Mediterranean (Sephardic) Jews.

• The most common inherited disease among blacks is sickle-cell disease.– It affects one of 400 African Americans.– It is caused by the substitution of a single

amino acid in hemoglobin.– When oxygen levels in the blood of an affected

individual are low, sickle-cell hemoglobin crystallizes into long rods.

– This deforms red blood cells into a sickle shape.

• This sickling creates a cascade of symptoms, demonstrating the pleiotropic effects of this allele.

• Doctors can use regular blood transfusions to prevent brain damage and new drugs to prevent or treat other problems.

• At the organismal level, the non-sickle allele is incompletely dominant to the sickle-cell allele.– Carriers are said to have the sickle-cell trait.– These individuals are usually healthy, although

some suffer some symptoms of sickle-cell disease under blood oxygen stress.

• At the molecule level, the two alleles are codominant as both normal and abnormal hemoglobins are synthesized.

• The high frequency of heterozygotes with the sickle-cell trait is unusual for an allele with severe detrimental effects in homozygotes.– Interestingly, individuals with one sickle-cell allele have

increased resistance to malaria, a parasite that spends part of its life cycle in red blood cells.

– In tropical Africa, where malaria is common, the sickle-cell allele is both a boon and a bane.• Homozygous normal individuals die of malaria,

homozygous recessive individuals die of sickle-cell disease, and carriers are relatively free of both.

• Its relatively high frequency in African Americans is a vestige of their African roots.

• Normally it is relatively unlikely that two carriers of the same rare harmful allele will meet and mate.

• However, consanguineous matings, those between close relatives, increase the risk.– These individuals who share a recent common

ancestor are more likely to carry the same recessive alleles.

• Most societies and cultures have laws or taboos forbidding marriages between close relatives.

• Although most harmful alleles are recessive, many human disorders are due to dominant alleles.

• For example, achondroplasia, a form of dwarfism, has an incidence of one case in 10,000 people.– Heterozygous individuals have the dwarf phenotype.– Those who are not achodroplastic dwarfs, 99.99% of the

population are homozygous recessive for this trait.

• Lethal dominant alleles are much less common than lethal recessives because if a lethal dominant kills an offspring before it can mature and reproduce, the allele will not be passed on to future generations.

• A lethal dominant allele can escape elimination if it causes death at a relatively advanced age, after the individual has already passed on the lethal allele to his or her children.

• One example is Huntington’s disease, a degenerative disease of the nervous system.– The dominant lethal allele has no obvious

phenotypic effect until an individuals is about 35 to 45 years old.

– The deterioration of the nervous system is irreversible and inevitably fatal.

• Any child born to a parent who has the allele for Huntington’s disease has a 50% chance of inheriting the disease and the disorder.

• Recently, molecular geneticists have used pedigree analysis of affected families to track down the Huntington’s allele to a locus near the tip of chromosomes 4.

• While some diseases are inherited in a simple Mendelian fashion due to alleles at a single locus, many other disorders have a multifactorial basis.– These have a genetic component plus a significant

environmental influence.– Multifactorial disorders include heart disease, diabetes,

cancer, alcoholism, and certain mental illnesses, such a schizophrenia and manic-depressive disorder.

– The genetic component is typically polygenic.

• At present, little is understood about the genetic contribution to most multifactorial diseases– The best public health strategy is education about the

environmental factors and healthy behavior.

• A preventative approach to simple Mendelian disorders is sometimes possible.

• The risk that a particular genetic disorder will occur can sometimes be assessed before a child is conceived or early in pregnancy.

• Many hospitals have genetic counselors to provide information to prospective parents who are concerned about a family history of a specific disease.

3. Technology is providing new tools for genetic testing and counseling

• Consider a hypothetical couple, John and Carol, who are planning to have their first child.

• In both of their families’ histories a recessive lethal disorder is present and both John and Carol had brothers who died of the disease.– While neither John and Carol nor their parents have the

disease, their parents must have been carriers (Aa x Aa).

– John and Carol each have a 2/3 chance of being carriers and a 1/3 chance of being homozygous dominant.

– The probability that their first child will have the disease = 2/3 (chance that John is a carrier) x 2/3 (chance that Carol is a carrier) x 1/4 (chance that the offspring of two carriers is homozygous recessive) = 1/9.

– If their first child is born with the disease, we know that John and Carol’s genotype must be Aa and they both are carriers.

– The chance that their next child will also have the disease is 1/4.

• Mendel’s laws are simply the rules of probability applied to heredity.– Because chance has no memory, the genotype of each

child is unaffected by the genotypes of older siblings.– While the chance that John and Carol’s first four

children will have the disorder (1/4 x 1/4 x 1/4 x 1/4), the likelihood of having a fifth child with the disorder is one chance in sixty four, still 1/4.

• Most children with recessive disorders are born to parents with a normal phenotype.

• A key to assessing risk is identifying if prospective parents are carriers of the recessive trait.

• Recently developed tests for several disorders can distinguish between normal phenotypes in heterozygotes from homozygous dominants.

• The results allow individuals with a family history of a genetic disorder to make informed decisions about having children.

• However, issues of confidentiality, discrimination, and adequate information and counseling arise.

• Tests are also available to determine in utero if a child has a particular disorder.

• One technique, amniocentesis, can be used beginning at the 14th to 16th week of pregnancy to assess the presence of a specific disease.– Fetal cells extracted from amniotic fluid are

cultured and karyotyped to identify some disorders.

– Other disorders can be identified from chemicals in the amniotic fluids.

• A second technique, chorionic villus sampling (CVS) can allow faster karyotyping and can be performed as early as the eighth to tenth week of pregnancy.– This technique extracts a sample of fetal tissue

from the chrionic villi of the placenta.– This technique is not suitable for tests requiring

amniotic fluid.

• Other techniques, ultrasound and fetoscopy, allow fetal health to be assessed visually in utero.

• Both fetoscopy and amniocentesis cause complications in about 1% of cases.– These include maternal bleeding or fetal death.– Therefore, these techniques are usually reserved for

cases in which the risk of a genetic disorder or other type of birth defect is relatively great.

• If fetal tests reveal a serious disorder, the parents face the difficult choice of terminating the pregnancy or preparing to care for a child with a genetic disorder.

• Some genetic tests can be detected at birth by simple tests that are now routinely performed in hospitals.

• One test can detect the presence of a recessively inherited disorder, phenyketonuria (PKU).– This disorder occurs in one in 10,000 to 15,000 births.– Individuals with this disorder accumulate the amino

acid phenylalanine and its derivative phenypyruvate in the blood to toxic levels.

– This leads to mental retardation.– If the disorder is detected, a special diet low in

phenyalalanine usually promotes normal development.